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TitleAutoantibody mimicry of hormone action at the thyrotropin receptor.
Journal, issue, pagesNature, Vol. 609, Issue 7928, Page 846-853, Year 2022
Publish dateAug 8, 2022
AuthorsBryan Faust / Christian B Billesbølle / Carl-Mikael Suomivuori / Isha Singh / Kaihua Zhang / Nicholas Hoppe / Antonio F M Pinto / Jolene K Diedrich / Yagmur Muftuoglu / Mariusz W Szkudlinski / Alan Saghatelian / Ron O Dror / Yifan Cheng / Aashish Manglik /
PubMed AbstractThyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' ...Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains.
External linksNature / PubMed:35940205 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 6.65 Å
Structure data

25758

7t9i

EMDB-25758, PDB-7t9i:
Native human TSH bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Method: EM (single particle) / Resolution: 2.9 Å

25762

7t9m

EMDB-25762, PDB-7t9m:
Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org 274179-0 Antagonist
Method: EM (single particle) / Resolution: 3.1 Å

25763

7t9n

EMDB-25763, PDB-7t9n:
M22 Agonist Autoantibody bound to Human Thyrotropin receptor in complex with miniGs399 (composite structure)
Method: EM (single particle) / Resolution: 2.9 Å

26795

7utz

EMDB-26795, PDB-7utz:
Human thyrotropin analog TR1402 bound to human Thyrotropin receptor in complex with miniGs399 (composite structure)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-27640: Org 2274179-0-bound Thyrotropin Receptor
Method: EM (single particle) / Resolution: 6.65 Å

EMDB-27647: Human thyrotropin analog TR1402 bound to human Thyrotropin receptor (extracellular domain map only)
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-27648: Human thyrotropin analog TR1402 bound to human Thyrotropin receptor (transmembrane domain and G protein map only)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-27649: Native human TSH bound to human Thyrotropin receptor (extracellular domain map only)
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-27650: Native human TSH bound to human Thyrotropin receptor (transmembrane domain and G protein map only)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-27651: M22 Fab bound to human Thyrotropin receptor (extracellular domain map only)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-27652: M22 Fab bound to human Thyrotropin receptor (transmembrane domain and G protein map only)
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-Z41:
(2S)-3-hydroxypropane-1,2-diyl dihexadecanoate

Source
  • homo sapiens (human)
  • human (human)
  • lama glama (llama)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / Thyroid-stimulating hormone receptor / Thyrotropin receptor / TSH / Thyroid / CS-17 Fab / M22 / autoantibody

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